Rotaviruses are the single most important etiological agents of severe diarrheal disease in infants and young children in both the developed and developing countries. These viruses are estimated to cause 30 to 50% of such illness in the US as well as world-wide. The consequences of such illness in developing countries are particularly grim because severe rotavirus disease in these regions is estimated to cause over 870,000 deaths each year. Thus, the need for an effective vaccine able to prevent severe rotavirus disease is clear. We have taken a "Jennerian" approach to vaccine development. This involves the use of a live animal virus that is: (i) antigenically related to its human virus target, (ii) attenuated for humans, and (iii) able to induce protective immunity against the human virus. Initial studies were performed with a simian rotavirus, rhesus rotavirus (RRV), that is closely related to human rotavirus serotype 3. Impressive protective effect was observed against serotype 3 human rotavirus disease but efficacy was variable against other rotavirus serotypes. We, therefore, developed a modified "Jennerian" approach that involved formulation of a quadrivalent rotavirus vaccine containing: (i) rhesus rotavirus (RRV) (VP7 serotype 3), and (ii) three human rotavirus-RRV reassortants, each possessing ten RRV genes and a single human rotavirus gene that encodes VP7 (the major protective antigen) serotype 1, 2, or 4 specificity. This has been a banner year because the results of two recently completed studies in the United States indicate that the quadrivalent formulation provided a high level of protective efficacy against severe rotavirus diarrheal disease. Under the auspices of our licensee, Wyeth-Ayerst Research, a multi-center (23 sites), three cell prospective, double- masked, placebo-controlled efficacy trial covering a period of two rotavirus seasons was performed. Protective efficacy against serious rotavirus disease was 82%. In addition there was a 78% reduction in need for medical visits for rotavirus disease. These encouraging observations were confirmed and expanded during a second large multi-center trial. Quadrivalent vaccine administered at a ten-fold higher dosage was 80% protective against severe rotavirus diarrheal disease. Most important was the observation that the quadrivalent vaccine was 100% effective in preventing dehydrating illness, the most severe form of rotavirus diarrhea.